Topical administration of acyclovir

ABSTRACT

The present invention provides a topical composition comprising (a) at least one delivery agent compound and (b) a acyclovir compound. Methods of treatment, and methods of preparing the topical composition are also provided.

CROSS-REFERENCE TO PRIOR APPLICATIONS

This is a Non Provisional U.S. Application of a InternationalApplication and a Provisional application, claiming the benefit ofPCT/US2007/067996 filed May 2, 2007; and U.S. Provisional ApplicationNo. 60/799,294 filed May 9, 2006.

FIELD OF THE INVENTION

The present invention relates to topical formulations containingacyclovir or a salt or analog thereof, such as acyclovir sodium, and adelivery agent compound.

BACKGROUND OF THE INVENTION

Skin conditions, such as herpes infections, are a widespread medicalproblem, with an increasing rate of prevalence. It has been reportedthat topically administered acyclovir, can be included in an effectiveprotocol for the treatment of herpes infections. The topical applicationof acyclovir(2-amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one) hasmultiple purposes including the treatment or prevention of mucocutaneousinfections such as oral labial (“fever blisters”), gingivostomatitis;and ophthalmically for keratoconjuntivitis and recurrent epitheliakeratitis.

For optimal performance a topical acyclovir product should maximize theacyclovir concentration delivered to the layer of the skin where thevirus resides. It is believed that in oral labial infection the virusresides in melanocytes at the epidermal-dermal junction. These cells lie60-140 μm beneath the skin surface. In-vivo measurement in humans ofacyclovir transport into the dermis has been performed using Zovirax®and microdialysis for monitoring delivered acyclovir (Br. J Dermatol.2003 March; 148(3):434-43; The role of stratum corneum and dermalmicrovascular perfusion in penetration and tissue levels ofwater-soluble drugs investigated by microdialysis; Morgan C J, Renwick AG, Friedmann P S). The IC₅₀ of Zovirax® cream (5%) against herpessimplex virus-1 isolates ranges from 0.02-13.5 mcg/mL and 0.01-9.9mcg/mL for herpes simplex virus-2. (2006 Physicians Desk Reference entryfor Zovirax cream.) In the study performed by Morgan et al., noacyclovir was detected in the dermis after application of acyclovir tointact skin. An acyclovir concentration of 3.9 μg/ml was achieved onlyafter removal of the stratum corneum and reduction of cutaneouscirculation by infusion of 0.0005% noradrenaline. (See Morgan, C J,ibid). Neither approach is suitable for a commercial product, butdemonstrates the role of the stratum corneum as the main barrier toacyclovir transport, and the rapid clearance of acyclovir from thedermis due to cutaneous circulation.

There is a need for a composition which provides concentrations ofacyclovir at the epidermal/dermal junction and would therefore increaseits therapeutic benefits in the treatment of herpes simplex virusinfection, including type 1 and type 2 herpes simplex viruses. Providinghigher levels of acyclovir to the epidermal/dermal junction via topicaladministration may also increase indications for topical therapy.

SUMMARY OF THE INVENTION

The present invention is a topical composition comprising (a) at leastone delivery agent compound, (b) an acyclovir component (e.g.,acyclovir, valacyclovir and nucleoside antiviral analogs thereof andpharmaceutically acceptable salts thereof and (c) a vehicle for topicaldelivery. In one embodiment of the invention, the composition includesan effective amount of the acyclovir component and a delivery agentcompound to treat or prevent the onset of a skin condition, particularlya skin condition caused or aggravated by herpes simplex virus types 1and 2 (HSV-1 and HSV-2).

The delivery agent compound improves the delivery of the acyclovircomponent to the epidermal/dermal junction, where the HSV virus resides.For instance, the topical composition including a delivery agentcompound can yield higher epidermis-layer concentrations of theacyclovir component over a period of time (e.g. 3 hours, 6 hours, 12hours or 24 hours) after a single administration than a similar topicalcomposition without the delivery agent compound.

The vehicle for topical delivery is a physiologically acceptable vehiclethat facilitates application of the acyclovir component and deliveryagent compound to the skin. For example, vehicle for topical deliverycan be semi-aqueous and oil-based solution or suspension. Suitablevehicles for topical delivery include, but are not limited to,isopropylmyristate (IPM), and polyethylene glycol (PEG) and watersolutions containing a thickening agent. The vehicle for topicaldelivery may be, for example, in the form of a cream, a gel, a lotion,an ointment, a suspension, an emulsion (e.g. an oil-in-water emulsion),depot delivery device and formulation as disclosed in U.S. Pat. Nos.7,018,649, 5,240,711, 5,225,199, 5,879,701, 6,894,078, 6,998,138,6,846,837, 6,620,435, and 6,586,473 which are hereby incorporated byreference in their entirety.

Another embodiment is a method for administering an acyclovir compound(e.g. Cicloferen® by LIOMONT Laboratories, S.A. de C.V.), an analoguethereof, or a mixture thereof to an animal (e.g., a patient) in needthereof, by topically administering the composition or dosage unitform(s) of the present invention to the animal.

Another embodiment is a method for administering a acyclovir compound(e.g. acyclovir), an analogue thereof, or a mixture thereof incombination with a topical analgesic (e.g., lidocaine, pramocaine,benzocaine, pramoxine, or mixtures thereof) to an animal (e.g., apatient) in need thereof, by topically administering the composition ordosage unit form(s) of the present invention to the animal.

Another embodiment is a method for administering a acyclovir compound(e.g. acyclovir), an analogue thereof, or a mixture thereof incombination with an antibiotic (e.g., aminoglycosides, cephalosporins,beta-lactams, chloramphenicol, glycopeptides, macrolides, penicillins,quinolones, sulfonamides, tetracylines, bacitracins, lincomycins,oxazolidinones, polymixins, rifamycins, streptogramins). Preferredantibiotics include neomycin, polymyxin B, gentamycin, amicacin,tobramycin, or mixtures thereof) to an animal (e.g., a patient) in needthereof, by topically administering the composition or dosage unitform(s) of the present invention to the animal.

Yet another embodiment is a method of treating skin conditions,including but not limited to herpes infections of the skin, mucousmembranes or eyes in an animal in need thereof (e.g., a patient) byadministering an effective amount of the composition or dosage unitform(s) of the present invention to the animal.

Yet another embodiment is a method of preparing a topical compositioncomprising mixing (a) at least one delivery agent compound, (b) at leastone the acyclovir compound, and (c) a vehicle for topical delivery.

Yet another embodiment provides topical acyclovir compositions with adelivery agent compound that achieves dermal acyclovir concentrations inthe IC₅₀ range, i.e., dermal acyclovir concentrations of at least about0.01 mcg/mL, or at least about 0.02 mcg/mL, or at least about 0.1mcg/mL, or at least about 1.0 mcg/mL, or at least about 2.0 mcg/mL, orat least about 3.0 mcg/mL, or at least about 4.0 mcg/mL, or at leastabout 5.0 mcg/mL, or at least about 6.0 mcg/mL, or at least about 7.0mcg/mL, or at least about 8.0 mcg/mL, or at least about 9.0 mcg/mL, orat least about 10.0 mcg/mL, or at least about 11.0 mcg/mL, or at leastabout 12.0 mcg/mL, or at least about 13.0 mcg/mL.

Yet another embodiment of the present invention provides an acylovirtopical formulation that has an acylovir component epidermal fluxenhancement factor of at least 1.1, or at least 4, or at least 8, or atleast 10, or at least 20, or least 40, or at least 80.

Yet another embodiment of the present invention is a topical compositionprepared from a base formulation comprising the commercial topicalacyclovir product Cicloferon®, available from Liomont S.K. de C.V(Colonia Centro Cuajimalpa, Mexico).

Yet another embodiment is a composition of the present inventioncomprising acyclovir and one or more delivery agent compounds in whichthe addition of the delivery agent compound provides an acyclovir influxinto the dermis at a rat of about 0.01 mcg/cm²-hr to about 15.8mcg/cm²-hr.

Yet another embodiment is a composition of the present inventioncomprising acyclovir and one or more delivery agent compound in whichprovides continuous influx of acyclovir through the epidermis for aperiod of time (e.g., 3 hours, 6 hours, 12 hours, 24 hours or 36 hours).

Yet another embodiment is a topical acyclovir composition (e.g.,Cicloferon®) further comprising SNAC and/or an alcohol.

Yet another embodiment is a composition of the present inventioncomprising Cicloferon and SNAC and an alcohol (e.g. ethanol).

Yet another embodiment is a composition of the present inventioncomprising Cicloferon and about 4% SNAC plus Ethanol and water in aratio of about 1:1.

Yet another embodiment is a composition of the present inventioncomprising Cicloferon and SNAC plus Ethanol and IPM.

Yet another embodiment is a composition of the present inventioncomprising Cicloferon and about 4% SNAC plus about up to 40% Ethanol andabout 3% water and about up to 30% IPM.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is cross section of skin layers.

FIGS. 2-11 are graphs of acyclovir flux over time through cadaver skin.

FIGS. 12 and 14 are graphs of ³H acyclovir flux over time throughcadaver skin.

FIGS. 13 and 15 are linear regression models of FIGS. 12 and 14.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term “hydrate” as used herein includes, but is not limited to, (i) asubstance containing water combined in the molecular form and (ii) acrystalline substance containing one or more molecules of water ofcrystallization or a crystalline material containing free water.

The term “solvate” as used herein includes, but is not limited to, amolecular or ionic complex of molecules or ions of a solvent withmolecules or ions of the delivery agent compound or salt thereof, orhydrate or solvate thereof.

The term “delivery agent” refers to any of the delivery agent compoundsdisclosed herein.

The term “SNAC” refers to the monosodium salt ofN-(8-[2-hydroxybenzoyl]-amino)caprylic acid.

The term “SNAD” refers to the monosodium salt ofN-(10-[2-hydroxybenzoyl]-amino)decanoic acid. The term “disodium salt ofSNAD” refers to the disodium salt ofN-(10-[2-hydroxybenzoyl]-amino)decanoic acid.

An “effective amount of the acyclovir component” is an amount of theacyclovir component which is effective to treat or prevent the conditionfor which it is administered in a living organism over some period oftime, e.g., an amount which provides a therapeutic effect. Indicationsfor which a acyclovir compound is administered are known to thoseskilled in the art, some of which are disclosed herein, and also includethose conditions that can be treated or prevented with a acyclovircompound which are to be later discovered.

An “effective amount of delivery agent” is an amount of the deliveryagent which enables and/or facilitates an increased concentration of theacyclovir component in the epidermis layer of the skin, as compared theconcentration of the acyclovir component in the epidermis uponadministration of the acyclovir component without the delivery agent.

The term “mean”, when preceding a pharmacokinetic value (e.g., meanpeak) represents the arithmetic mean value of the pharmacokinetic valueunless otherwise specified.

The term “acylovir component epidermal flux enhancement factor” refersto the ratio of (a):(b), wherein (a) is the acyclovir component (e.g.acyclovir or valacyclovir) flux through the epidermis for a compositioncontaining an additive to increase flux (e.g. a delivery agent compoundor an alcohol) and (b) is the acyclovir component flux through theepidermis for the otherwise same composition that does not contain theadditive to increase flux.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the,” include plural referents unless the context clearly indicatesotherwise. Thus, for example, reference to “a molecule” includes one ormore of such molecules, “a reagent” includes one or more of suchdifferent reagents, reference to “an antibody” includes one or more ofsuch different antibodies, and reference to “the method” includesreference to equivalent steps and methods known to those of ordinaryskill in the art that could be modified or substituted for the methodsdescribed herein.

The term “about” generally means within 10%, preferably within 5%, andmore preferably within 1% of a given value or range.

The terms “alkyl” and “alkenyl” as used herein include linear andbranched alkyl and alkenyl substituents, respectively.

The term “patient” as used herein refers to a mammal and preferably ahuman.

The phrase “pharmaceutically acceptable” refers to additives orcompositions that are physiologically tolerable and do not typicallyproduce an allergic or similar untoward reaction, such as rash, welts,swelling, increased sensitivity, and the like, when administered to theskin or mucous membranes of a patient.

Acyclovir Component

The term “acyclovir” refers to 9-(2-hydroxyethoxymethyl) guanine.Suitable salts (e.g., pharmaceutically acceptable salts) and esters ofacyclovir are described in U.S. Pat. No. 4,199,574, which is herebyincorporated by reference, and include, but are not limited to, sodiumacyclovir and acyclovir valerate. Acyclovir also forms acid additionsalts; such as with hydrochloric, sulphuric, phosphoric, maleic,fumaric, citric, tartaric, lactic and acetic acid.

A synthesis of acyclovir is disclosed in U.S. Pat. No. 4,199,574, whichis hereby incorporated by reference. Acyclovir is commercially availablefrom GlaxoSmithKline (Research Triangle Park, N.C.) under the tradenameZovirax®.

Any prodrug which is converted in vivo to 9-(2-hydroxyethoxymethyl)guanine can also be used. As used herein, the term “acyclovir” or“acyclovir component” includes prodrugs of acyclovir. The term “prodrug”as used herein includes pharmaceutically acceptable salts of the drug.Acyclovir prodrugs include, substituted purines of the formula:

or salts thereof, wherein:

R is hydrogen, hydroxy, or amino;

X is oxygen or sulphur;

Y is hydrogen or hydroxymethyl; and

Z is —H, C₁₋₁₆ alkyl, or —OCOCH(R₁)NH₂, wherein R₁ is —CH[CH₃]₂.

Suitable acyclovir prodrugs, include but are not limited to, thosedescribed in U.S. Pat. Nos. 4,609,662, 4,758,572 and 4,957,924, all ofwhich are hereby incorporated by reference. A non-limiting example ofsuch a prodrug is2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester(valacyclovir) and its pharmaceutically acceptable salts (e.g.valacyclovir hydrochloride). Valacyclovir is commercially available asits hydrochloride salt from GlaxoSmithKline (Research Triangle Park,N.C.) under the tradename Valtrex™.

Therapeutically effective amounts of a acyclovir for use in treatment ofall conditions and disorders described herein, is an amount sufficientto suppress or alleviate conditions associated with the viral infection.As will be recognized by those in the field, an effective amount oftherapeutic agent will vary with many factors including the potency ofthe acyclovir or salt, ester, or prodrug thereof, the age and weight ofthe patient, and the severity of the condition or disorder to betreated.

According to one embodiment, the compositions of the present inventioncontain from about 0.5% to about 20% by weight of an acyclovircomponent. According to another embodiment, the composition containsfrom about 1% to about 10% by weight, or from about 3% to about 6%, orfrom about 4% to about 5% by weight of an acylovir component.

The acyclovir and delivery agent compound may be administered separatelyor together with one or more other active agents. For example, theacyclovir and delivery agent compound may be administered separately ortogether with compounds or compositions that exhibit antiviral activity,such as compounds used to treat retroviral infections (particularly HIVinfections), e.g., 3′-azido-3′-deoxythymidine (AZT) and/or compounds orcompositions that exhibit activity as ribonucleotide reductaseinhibitors. Suitable ribonucleotide reductase inhibitors include, butare not limited to, thiocarbonohydrazone ribonucleotide reductaseinhibitors, such as those disclosed in U.S. Pat. No. 5,393,883, which ishereby incorporated by reference. Additional antiviral agents that maybe included in the compositions of the present invention includedocosanol, penciclovi, fomivirsen and trifluridine.

Delivery Agent Compounds

In one embodiment of the present invention, the delivery agent compoundhas the following structure, or a pharmaceutically acceptable saltthereof:

wherein

Ar is phenyl or naphthyl;

Ar is optionally substituted with one or more of —OH, halogen, C₁-C₄alkyl, C₁-C₄ alkenyl, C₁-C₄ alkoxy or C₁-C₄ haloalkoxy;

R⁷ is C₄-C₂₀ alkyl, C₄-C₂₀ alkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl)phenyl, (C₁-C₁₀ alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl, (C₁-C₁₀alkenyl) naphthyl, phenyl(C₁-C₁₀ alkyl), phenyl(C₁-C₁₀ alkenyl),naphthyl(C₁-C₁₀ alkyl), or naphthyl(C₁-C₁₀ alkenyl);

R⁸ is hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl, C₁ to C₄ alkoxy, orC₁-C₄ haloalkoxy;

R⁷ is optionally substituted with C₁ to C₄ alkyl, C₂ to C₄ alkenyl, C₁to C₄ alkoxy, C₁-C₄ haloalkoxy, —OH, —SH, —CO₂R⁹, or any combinationthereof;

R⁹ is hydrogen, C₁ to C₄ alkyl, or C₂ to C₄ alkenyl; and

R⁷ is optionally interrupted by oxygen, nitrogen, sulfur or anycombination thereof.

In one embodiment, the delivery agent compounds are not substituted withan amino group in the position alpha to the acid group.

Suitable delivery agent compounds include, but are not limited to,N-(8-[2-hydroxybenzoyl]-amino)caprylic acid and salts thereof, e.g., asodium salt of N-(8-[2-hydroxybenzoyl]-amino)caprylic acid, such as amono- or di-sodium salt, N-(8-[2-hydroxybenzoyl]-amino) decanoic acidand pharmaceutically acceptable salts thereof, including its monosodiumsalt, 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (also known as4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate) and pharmaceuticallyacceptable salts thereof, including its sodium salt (e.g., monosodiumsalt), N-(8-[2-hydroxy-5-chlorobenzoyl]-amino)octanoic acid (also knownas 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid)) andpharmaceutically acceptable salts thereof, including its monosodiumsalt, and 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid andpharmaceutically acceptable salts thereof, including its monosodiumsalt.

According to one embodiment, R⁷ in Formula A is selected from C₈-C₂₀alkyl, C₈-C₂₀ alkenyl, phenyl, naphthyl, (C₁-C₁₀ alkyl) phenyl, (C₁-C₁₀alkenyl)phenyl, (C₁-C₁₀ alkyl) naphthyl, (C₁-C₁₀ alkenyl) naphthyl,phenyl(C₁-C₁₀ alkyl), phenyl(C₁-C₁₀ alkenyl), naphthyl(C₁-C₁₀ alkyl),and naphthyl(C₁-C₁₀ alkenyl).

According to another embodiment, R⁷ in Formula A is selected from C₈-C₂₀alkyl, and C₈-C₂₀ alkenyl.

In another embodiment of the present invention, the delivery agentcompound has the following structure, or a pharmaceutically acceptablesalt thereof:

wherein

R¹, R², R³, and R⁴ are independently H, —OH, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₁-C₄ alkoxy, —C(O)R⁸, —NO₂, —NR⁹R¹⁰, or —N⁺R⁹R¹⁰R¹¹(R¹²);

R⁵ is H, —OH, —NO₂, halogen, —CF₃, —NR¹⁴R¹⁵, —N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻, amide,C₁-C₁₂ alkoxy, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, carbamate, carbonate, urea,or —C(O)R¹⁸;

R⁵ is optionally substituted with halogen, —OH, —SH, or —COOH;

R⁵ is optionally interrupted by O, N, S, or —C(O)—;

R⁶ is a C₁-C₁₂ alkylene, C₂-C₁₂ alkenylene, or arylene;

R⁶ is optionally substituted with a C₁-C₄ alkyl, C₂-C₄ alkenyl, C₁-C₄alkoxy, —OH, —SH, halogen, —NH₂, or —CO₂R⁸;

R⁶ is optionally interrupted by O or N;

R⁷ is a bond or arylene;

R⁷ is optionally substituted with —OH, halogen, —C(O)CH₃, —NR¹⁰R¹¹, or—N⁺R¹⁰R¹¹R¹²(R¹³)⁻;

each occurrence of R⁸ is independently H, C₁-C₄ alkyl, C₂-C₄ alkenyl, or—NH₂;

R⁹, R¹⁰, R¹¹, and R¹² independently H or C₁-C₁₀ alkyl;

R¹³ is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;

R¹⁴, R¹⁵ and R¹⁶ are independently H, C₁-C₁₀ alkyl, C₁-C₁₀ alkylsubstituted with —COOH, C₂-C₁₂ alkenyl, C₂-C₁₂ alkenyl substituted with—COOH, or —C(O)R¹⁷;

R¹⁷ is —OH, C₁-C₁₀ alkyl, or C₂-C₁₂ alkenyl; and

R¹⁸ is H, C₁-C₆ alkyl, —OH, —NR¹⁴R¹⁵, or N⁺R¹⁴R¹⁵R¹⁶(R¹³)⁻.

In one particular embodiment, when R¹, R², R³, R⁴, and R⁵ are H, and R⁷is a bond then R⁶ is not a C₁-C₆, C₉ or C₁₀ alkyl.

In another embodiment, when R¹, R², R³, and R⁴ are H, R⁵ is —OH, and R⁷is a bond then R⁶ is not a C₁-C₃ alkyl.

In yet another embodiment, when at least one of R¹, R², R³, and R⁴ isnot H, R⁵ is —OH, and R⁷ is a bond, then R⁶ is not a C₁-C₄ alkyl.

In yet another embodiment, when R¹, R², and R³ are H, R⁴ is —OCH₃, R⁵ is—C(O)CH₃, and R⁶ is a bond then R⁷ is not a C₃ alkyl.

In yet another embodiment, when R¹, R², R⁴, and R⁵ are H, R³ is —OH, andR⁷ is a bond then R⁶ is not a methyl.

In yet another embodiment, R⁶ of Formula B is a C₈-C₁₂ alkylene, C₈-C₁₂alkenylene, or arylene.

In yet another embodiment of the present invention, the delivery agentcompound has the following structure or a pharmaceutically acceptablesalt thereof:

wherein

R¹, R², R³, R⁴ and R⁵ are independently H, —CN, —OH, —OCH₃, or halogen,at least one of R¹, R², R³, R⁴ and R⁵ being —CN; and

R⁶ is a C₁-C₁₂ linear or branched alkylene, a C₁-C₁₂ linear or branchedalkenylene, a C₁-C₁₂ linear or branched arylene, an alkyl(arylene) or anaryl(alkylene).

According to one embodiment, when R¹ is —CN, R⁴ is H or —CN, and R², R³,and R⁵ are H, then R⁶ is not methylene ((CH₂)₁).

In another embodiment, R⁶ of Formula C is a C₈-C₁₂ linear or branchedalkylene, a C₈-C₁₂ linear or branched alkenylene, an arylene, analkyl(arylene) or an aryl(alkylene).

In yet another embodiment, R⁶ of Formula C is a C₈-C₁₂ linear orbranched alkylene, a C₈-C₁₂ linear or branched alkenylene

Other suitable delivery agent compounds are disclosed in U.S. Pat. No.6,627,228, which is hereby incorporated by reference.

In embodiments of the present invention, delivery agent compounds to beused in the topical composition along with the acyclovir compoundinclude, but are not limited to, a polymeric delivery agent comprising apolymer conjugated to a modified amino acid or derivative thereof via alinkage group selected from the group consisting of —NHC(O)NH—,—C(O)NH—, —NHC(O)—, —OOC—, —COO—, —NHC(O)O—, —OC(O)NH—, —CH₂NH—,—NHCH₂—, —CH₂NHC(O)O—, —OC(O)NHCH₂—, —CH₂NHCOCH₂O—, —OCH₂C(O)NHCH₂—,—NHC(O)CH₂O—, —OCH₂C(O)NH—, —NH—, —O—, and carbon-carbon bond. In oneembodiment, the polymeric delivery agent is not a polypeptide orpolyamino acid. In another embodiment, the modified amino acid has thestructure of formula A, B, or C. In one embodiment, the polymericdelivery agent includes a modified amino acid having the structure:

which is conjugated via a —COO group to a polymer having monomersderived from polyethylene glycol.

In one embodiment, the polymeric delivery agent is a modified amino acidhaving the structure of Formula D conjugated via a —COO group to apolymer having the structure:—CH₂CH₂O(CH₂CH₂O)_(x)CH₂CH₂O—Y,wherein

x is from 1-14; and

Y is H or CH₃.

According to one embodiment, the polymeric delivery agent is compoundhaving the structure of Formula D conjugated via a —COO group to apolymer having the structure:—CH₂CH₂O(CH₂CH₂O)_(x)CH₂CH₂O—Y,wherein

x is 1-9; and

Y is CH₃ or H. For example, the polymeric delivery agent can be8-(2-hydroxybenzoylamino)-octanoic acid2-{2-[2-(2-{2-[2-(2-methoxyethoxy)ethoxy]ethoxy}-ethoxy)ethoxy]ethoxy}ethylester.

In one embodiment, the delivery agent compound is PEGylated SNAC with anaverage of about 6-9 or about 7-8 (e.g. 7.3) repeating ethylene oxidegroups and having a molecular weight of about 500-800 (e.g. 600)daltons.

Delivery agent compounds of the present invention include compounds asshown below and pharmaceutically acceptable salts thereof:

wherein:

R₁ is —(CH₂)_(m)—R₈, wherein m=0 or 1;

R₂-R₆ are independently selected from hydrogen, hydroxyl, halogen, C₁-C₄alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄ alkoxy, and cyano;

R₇ is selected from C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, and C₂-C₁₀ alkynyl;

R₈ is selected from cyclopentyl, cyclohexyl and phenyl, wherein when R₈is a phenyl, m=1; and

R₈ is optionally substituted with C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen orhydroxyl, or a combination thereof.

Other delivery agent compounds of the present invention include those ofthe formula:

and pharmaceutically acceptable salts thereof, wherein:

R₁ is a C₁-C₆ alkyl, or C₂-C₆ alkenyl,

R₂-R₆ are independently chosen from the group consisting of hydrogen,hydroxyl, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₄alkoxy, and cyano, and

R₇ is selected from the group consisting of C₁-C₁₀ alkyl, C₂-C₁₀alkenyl, and C₂-C₁₀ alkynyl.

Other delivery agent compounds of the present invention include those ofthe formula:

and pharmaceutically acceptable salts thereof, wherein

n=1 to 9, and

R₁ to R₅ are independently hydrogen, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₂to C₄ alkenyl, halogen, hydroxyl, —NH—C(O)—CH₃, or —O—C₆H₅.

Other delivery agent compounds of the present invention include those ofthe formula:

and pharmaceutically acceptable salts thereof, wherein

R₁ to R₄ are independently hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl,halogen, C₁ to C₄ alkoxy, or hydroxyl.

Other delivery agent compounds of the present invention include those ofthe formula:

and pharmaceutically acceptable salts thereof, wherein

one of R1 to R5 has the generic structure—(CH2)n-COOHwhere n=0-6;

the remaining four members of R₁ to R₅ are independently hydrogen, C₁ toC₄ alkyl, C₂ to C₄ alkenyl, halogen, C₁ to C₄ alkoxy, or hydroxyl; and

R₆-R₁₀ are independently hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl,halogen, C₁ to C₄ alkoxy, or hydroxyl.

and pharmaceutically acceptable salts thereof, wherein

n=1 to 9; and

R₁ to R₉ are independently hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl,halogen, C₁ to C₄ alkoxy, or hydroxyl.

Other delivery agent compounds of the present invention include those ofthe formula:

and pharmaceutically acceptable salts thereof, wherein

R₁-R₅ are independently hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl,halogen, C₁ to C₄ alkoxy, hydroxyl, or —O—(CH2)n—COOH (where n is 1 to12);

at least one of R₁ to R₅ has the generic structure—O—(CH2)n-COOHwhere n=1-12; and

R₆-R₁₀ are independently hydrogen, C₁ to C₄ alkyl, C₂ to C₄ alkenyl,halogen, C₁ to C₄ alkoxy, or hydroxyl. International Application Nos.PCT/US2005/017339 and PCT/US2005/017309, filed May 16, 2005 and theirpriority documents, U.S. Provisional Application No. 60/576,088, filedJun. 1, 2004, U.S. Provisional Application No. 60/576,397, filed Jun. 1,2004, U.S. Provisional Application No. 60/576,105, filed Jun. 1, 2004,U.S. Provisional Application No. 60/571,090, filed May 14, 2004, U.S.Provisional Application No. 60/571,092, filed May 14, 2004, U.S.Provisional Application No. 60/571,195, filed May 14, 2004, U.S.Provisional Application No. 60/571,194, filed May 14, 2004, U.S.Provisional Application No. 60/571,093, filed May 14, 2004, U.S.Provisional Application No. 60/571,055, filed May 14, 2004, U.S.Provisional Application No. 60/571,151, filed May 14, 2004, U.S.Provisional Application No. 60/571,315, filed May 14, 2004, U.S.Provisional Application No. 60/571,144, filed May 14, 2004, and U.S.Provisional Application 60/571,089, filed May 14, 2004, are herebyincorporated by reference in their entirety.

The delivery agent compound may be any of those described in U.S. Pat.Nos. 6,846,844, 6,699,467, 6,693,208, 6,693,208, 6,693,073, 6,663,898,6,663,887, 6,646,162, 6,642,411, 6,627,228, 6,623,731, 6,610,329,6,558,706, 6,525,020, 6,461,643, 6,461,545, 6,440,929, 6,428,780,6,413,550, 6,399,798, 6,395,774, 6,391,303, 6,384,278, 6,375,983,6,358,504, 6,346,242, 6,344,213, 6,331,318, 6,313,088, 6,245,359,6,242,495, 6,221,367, 6,180,140, 5,541,155, 5,693,338, 5,976,569,5,643,957, 5,955,503, 6,100,298, 5,650,386, 5,866,536, 5,965,121,5,989,539, 6,001,347, 6,071,510, and 5,820,881; U.S. PublishedApplication Nos. 20050009748, 20040110839, 20040106825, 20040068013,20040062773, 20040022856, 20030235612, 20030232085, 20030225300,20030198658, 20030133953, 20030078302, 20030072740, 20030045579,20030012817, 20030008900, 20020155993, 20020127202, 20020120009,20020119910, 20020102286, 20020065255, 20020052422, 20020040061,20020028250, 20020013497, 20020001591, 20010039258, 20010003001International Publication Nos. WO 2005/020925, WO 2004/104018, WO2004/080401, WO 2004/062587, WO 2003/057650, WO 2003/057170, WO2003/045331, WO 2003/045306, WO 2003/026582, WO 2002/100338, WO2002/070438, WO 2002/069937, WO 02/20466, WO 02/19969, WO 02/16309, WO02/15959, WO 02/02509, WO 01/92206, WO 01/70219, WO 01/51454, WO01/44199, WO 01/34114, WO 01/32596, WO 01/32130, WO 00/07979, WO00/59863, WO 00/50386, WO 00/47188, WO 00/40203, and WO 96/30036, all ofwhich are hereby incorporated by reference in their entirety.

Non-limiting examples of delivery agent compounds includeN-(8-[2-hydroxybenzoyl]-amino)caprylic acid,N-(10-[2-hydroxybenzoyl]-amino)decanoic acid,8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,4-[(2-hydroxy-4-chlorobenzoyl)amino]butanoate,8-(2,6-dihydroxybenzoylamino)octanoic acid,8-(2-hydroxy-5-bromobenzoylamino)octanoic acid,8-(2-hydroxy-5-chlorobenzoylamino)octanoic acid,8-(2-hydroxy-5-iodobenzoylamino)octanoic acid,8-(2-hydroxy-5-methylbenzoylamino)octanoic acid,8-(2-hydroxy-5-fluorobenzoylamino)octanoic acid,8-(2-hydroxy-5-methoxybenzoylamino)octanoic acid,8-(3-hydroxyphenoxy)octanoic acid, 8-(4-hydroxyphenoxy)octanoic acid,6-(2-cyanophenoxy)hexanoic acid,8-(2-Hydroxyphenoxy)octyl-diethanolamine, 8-(4-hydroxyphenoxy)octanoate,8-(4-hydroxyphenoxy)octanoate,8-(2-hydroxy-4-methoxybenzoylamino)octanoic acid,8-(2-hydroxy-5-methoxybenzoylamino)-octanoic acid, and salts thereof.Preferred salts include, but are not limited to, monosodium and disodiumsalts.

The delivery agent compounds may be in the form of the carboxylic acidor pharmaceutically acceptable salts thereof, such as sodium salts, andhydrates and solvates thereof. The salts may be mono- or multivalentsalts, such as monosodium salts and disodium salts. The delivery agentcompounds may contain different counter ions chosen for example due totheir effect on modifying the dissolution profile of the delivery agentcompound.

The delivery agent compounds may be prepared by methods known in theart, such as those discussed in the aforementioned publications (e.g.,International Publication Nos. WO 98/34632, WO 00/07979, WO 01/44199, WO01/32596, WO 02/20466, and WO 03/045306). SNAC, SNAD, and the free acidand other salts thereof may be prepared by any method known in the art,such as those described in U.S. Pat. Nos. 5,650,386 and 5,866,536.

Salts of the delivery agent compounds of the present invention may beprepared by methods known in the art. For example, sodium salts may beprepared by dissolving the delivery agent compound in ethanol and addingaqueous sodium hydroxide.

The delivery agent compound may be purified by recrystallization or byfractionation on one or more solid chromatographic supports, alone orlinked in tandem. Suitable recrystallization solvent systems include,but are not limited to, acetonitrile, methanol, and tetrahydrofuran.Fractionation may be performed on a suitable chromatographic supportsuch as alumina, using methanol/n-propanol mixtures as the mobile phase;reverse phase chromatography using trifluoroacetic acid/acetonitrilemixtures as the mobile phase; and ion exchange chromatography usingwater or an appropriate buffer as the mobile phase. When anion exchangechromatography is performed, preferably a 0-500 mM sodium chloridegradient is employed.

In one embodiment, the weight ratio of delivery agent to acyclovircompound ranges from about 0.1:1 to about 2000:1. The weight ratio mayvary according to the acyclovir compound delivered and the particularindication for which it is administered.

Vehicles for Topical Delivery

Embodiments of the present invention include a cream or ointment base asa vehicle for topical delivery. This is particularly true where thecomposition is used on dry or peeling skin and when a moisturizingvehicle may otherwise be desirable. Suitable bases include lanolin,SILVADENE™ (silver sulfadiazine) (Hoechst Marion Roussel, Kansas City,Mo.), particularly for treatment of burns, AQUAPHOR™ (Duke Laboratories,South Norwalk, Conn.), and like bases.

Viscosity building agents may also serve as vehicles for topicaldelivery, and can be added to aqueous or oil based solutions to form acream or gel. Examples of viscosity building agents include such aspolyethylene glycol, gelatin, chitosan and its derivatives, hydrophiliccellulose (preferably a hydroxyalkylcellulose and more preferably,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose orthe like or a mixture thereof), and polyacrylate-polyacrylic acidpolymers (e.g., Carbomers and the like).

Other vehicles for topical delivery include, but are not limited to,urea-based emollients, petroleum-based ointments, paste, lotion, liquidparaffin, lanolin, beeswax, vegetable oil, glycerin monostearate, higheralcohols, oil-in-water emulsion, or a water-in-oil emulsion. Furtherexamples of vehicles for topical delivery include those topical agentsdisclosed in U.S. Pat. Nos. 7,018,660 and 6,994,863, both of which arehereby incorporated by reference in their entirety.

Delivery Systems

The composition of the present invention comprises one or more deliveryagent compounds of the present invention and/or one or more acyclovircompounds. The delivery agent compound and acyclovir compound aretypically mixed prior to administration to form an administrationcomposition (which may comprise a unit dosage form).

The administration composition of the present invention may also containother active ingredients such as those discussed in InternationalPublication No. 99/60997 which is hereby incorporated by reference,anti-allergic medications (e.g. oxatamide), glucocorticoids orcorticosteroids (e.g. betamethasone valerate, dexamethasone,triamcinolone acetonide, clobetasone butyrate, hydrocortisone andtriamcinolone).

The administration compositions of the present invention may alsocontain nonsteroidal anti-inflammatory agents, including, but notlimited to, flurbiprofen and ketorolace.

The administration composition may also contain other active ingredientssuch as antibiotics, pain relievers and local anesthetics. Limitingexample include lidocaine, benzocaine, articaine, chlorprocaine,cocaine, dydloninem, proparacaine, mepivacaine, prilocaine, procaine,tetracaine, and pramoxine.

The administration composition may also contain other ingredients knownto provide therapeutic effects to skin. These ingredients include, butare not limited to, aloe, antioxidants, moisturizers or humectants,vitamins, surfactants, hydroxy acids, proteolytic enzymes, skinlightening agents (e.g. melanin inhibitors, melanin bleaches),sunscreen, colorants, perfumes, preservatives, pigments, antisepticagents, and toners. Any of the ingredients listed in the InternationalCosmetic Ingredient Dictionary and Handbook, 9^(th) Ed. 2002, by TheCosmetic Toiletry Fragrance Association (ISBN 1882621298), which ishereby incorporated by reference in its entirety, may be incorporatedinto the administration composition of the present invention.

The administration composition is typically applied topically to atargeted area of skin. The administration composition may be applieddaily, for typically at least several days. However, more frequentapplication is also contemplated. For example, in the treatment ofinjured tissue, such as a rash, or an allergy-induced skin problem, itmay be desirable to continuously maintain the administration compositionon the affected area during healing, with applications of theadministration composition from two to four times a day or morefrequently. Use may also be for extended periods, including years.

If desired, it is possible to incorporate either aqueous or water-oilbase compositions in bandages or other wound dressings to provide forcontinuous exposure of the affected area to the topical composition.Aerosol applicators may also find use.

The amount of the acyclovir compound in the administration compositionis an effective amount of acyclovir compound, which can be determined bythose skilled in the art depending on the condition for which it isadministered. The unit dosage form may comprise, for example, from about0.01% to 10%, or about 0.01% to about 7%, or about 0.5% to about 4.0% ofacyclovir compound. In alternative embodiments, an acyclovir compound isadded until the administration composition is saturated with theacyclovir compound. In aqueous vehicles, this may correlate to aacyclovir compound concentration of about 5%. In semi-aqueous vehicles,such as isopropylmyristate, this may correlate to about 0.01% acyclovircompound concentration. In other vehicles, such as a PEG/Water vehicle,the acyclovir compound concentration is about 3% upon saturation of theadministration composition.

The present invention provides, in addition to compositions as describedabove, a method for improving skin conditions. The method comprisesapplying the topical composition to an affected area. Herpes simplex,herpes zoster, can be treated or prevented by administering an effectiveamount of the composition or dosage unit form(s) of the presentinvention to the animal.

EXAMPLES

The following examples illustrate the invention without limitation. Allparts are given by weight unless otherwise indicated. Acyclovir andCicloferon® used in the study was obtained from Liomont S.A. de C.V. Allexcipients were commercially purchased. All delivery agents weresynthesized at Emisphere Technologies, Inc. (Tarrytown, N.Y.).

Human cadaver skin was obtained from the N.Y. Firefighters Skin Bank atNew York Presbyterian Hospital. It was delivered frozen at −70° C., andstored in a media of 80/10/10 balanced salt solution/calf serum/glycerolwith the antimicrobials sodium oxacillin and gentamicin. The allograftskin was suitable for use in the treatment of burn victims.

Preparation of Human Cadaver Skin

A heat separation process was used to separate the epidermis from thedermis prior to skin permeation studies. The cadaver skin was firstrapidly thawed in a water bath and rinsed in DI water. The skin was thenplaced in a beaker of DI water at 60-62° C. for 90-120 seconds. Manualseparation of the epidermis from the dermis was then possible. Eachlayer was then floated in a tray of DI water, then removed on a clearsilicone treated PET support film. Skin not used immediately wasrefrozen at −76° C. for later studies.

Equipment & Apparatus for Skin Permeation Rate Studies

Skin permeation studies were performed using two compartment diffusioncells. Two different types of cells were used, a horizontal Franz typecell, and a horizontal in line flow through cell. The Franz cells weremagnetically stirred, jacketed and kept at 33° C. with a recirculatingheater. The flow through cells had no provision for stirring, and wereconverted for non-flow use by means of luer fittings and valves.Temperature was maintained by placing the flow through cells and theirholder in an oven at 33° C. Sampling was performed manually at intervalsfrom 2-20 hours. Typical study duration was 2-3 days. A pH 7.4 phosphatebuffer was used as the receptor, and it was completely exchanged at eachsample point.

Skin Permeation/Content Experiments

The permeation cells were equilibrated at 33° C., and the skin mountedbetween the two halves of the cell. The epidermis, or epidermis & dermiswere used depending on the analysis technique. The skin was allowed toequilibrate with the receptor buffer in the cells for 30-90 minutesprior to the study start. The acyclovir topical composition was placedin the cell donor chamber at the study start. At the conclusion of thestudy, the acyclovir donor was rinsed from the cell, and the celldisassembled. The epidermis (and/or dermis) was removed from the cell,rinsed again, then extracted and assayed for acyclovir content.

Drug Assay Methods

Collected samples from skin permeation/content studies were assayed foracyclovir and/or SNAC content by separate HPLC assay methods. Bothmethods were isocratic and used UV detection and conventional C8 and C18columns. Specific details on each method can be found in Table 1 below:

TABLE 1 HPLC assay methods Acyclovir SNAC column Phenomenex HigginsAnalytical #KS-0546-C185 #00G-0081-E0 5 micron IB-Sil C8, 5 micron 50 ×4.6 mm 250 × 4.6 mm ratio A/B, 90/10 A/B, 55/45 Sol. A 25 mM KH₂PO₄acetonitrile/water/acetic acid/1N HCI (3.403 g/l) + ~150 100/891/4/5 μl85% phosphoric acid to pH 2.75 Sol. B methanol acetonitrile/water/aceticacid/697/300.3 flow isocratic 1.0 ml/min isocratic 1.0 ml/min rate

Formulations Used in Skin Permeation Studies

Topical dosage forms prepared were in the form of polymer thickened gelsand suspensions. The excipients, delivery agent compound, and thickenerwere typically prepared first by means of an impeller type mixer orhomogenizer for two minutes. For non-Cicloferon-based formulations, thedrug was added last, and blended for two minutes using a homogenizer, ormanually with a positive displacement pipette. The addition order wasreversed with Cicloferon based formulations. The following formulationswere prepared:

TABLE 2 Formulations Tested in Acyclovir Permeation and RetentionStudies Formulation Ingredient Amount (wt %) A hydroxypropylcellulose2.0 ethanol 38.9 water 49.9 triethanolamine 0.5 SNAC (delivery agent)4.1 Acyclovir 4.6 B (control) Cicloferon 100 C Cicloferon 95.0 SNAC 5.0D Cicloferon 90.9 Pegylated SNAC 9.1 E Cicloferon 97.0 SNAC 3.0 FCicloferon 74.2 Ethanol 21.7 SNAC 4.1 G Cicloferon 67.3 Ethanol 4.5 SNAC17.9 isopropylmyristate (IPM) 10.2 H ethanol 41.6 IPM 40.8 water 4.0hydroxypropylcellulose 2.0 ethylcellulose N22F 9.4 Acylovir 2.3 Ihydroxypropylcellulose 1.9 ethanol 41.5 water 52.2 triethanolamine 0.5SNAC 7.2 IPM 4.5 acyclovir 3.8 J hydroxypropylcellulose 2.1 ethanol 41.5water 52.2 triethanolamine 0.5 acyclovir 3.7 K hydroxypropylcellulose0.6 ethanol 11.2 water 14.0 triethanolamine 0.1 IPM 71.1 acyclovir 3.0 Lhydroxypropylcellulose 2.0 ethanol 54.5 water 34.8 triethanolamine 0.5SNAC 4.0 acyclovir 4.2 M hydroxypropylcellulose 2.0 ethanol 23.3 water66.0 triethanolamine 0.5 SNAC 4.0 acyclovir 4.2 N hydroxypropylcellulose2.0 ethanol 38.9 water 49.9 triethanolamine 0.5 SNAC 4.1 acyclovir 4.6

Acyclovir Skin Permeation and Dermal/Epidermal Content

The performance of various formulation described below was measured viathe acyclovir skin flux rate as compared to the control Cicloferon-onlyformulation (Formulation B). The epidermal acyclovir concentrations werealso measured. These results are shown below in Tables 3 and 4:

TABLE 3 Acyclovir skin permeation studies: Acyclovir Acyclovir Acyclovirflux Flux ratio Amount # retention -- retention -- through (ComparedAnalysis Applied cells epidermis dermis epidermis Skin to control ofFormulation Technique (μL/cm2) (n) (μg/g) (μg/g) (μg/cm2 * hr)) DonorCells same donor) A A 160 4 420 ± 180 130 ± 30  0.98 ± 0.23 A Crown42.61 B A 105 4 160 ± 160 20 ± 30 0.023 ± 0.015 A in-line NA C A 210 5 9 ± 17 0.5 ± 0.6 0.15 ± 0.14 A in-line 6.521 D A 105 3 <LD 20 ± 30 0.2± 0.2 A in-line 8.70 E A 210 5 1030 ± 900  250 ± 90  8.8 ± 7.0 B in-line14.67 E B 320 6 — — 6.70 ± 3.80 B Crown 11.17 B B 320 4 — — 0.60 ± 0.66B Crown NA E C 37.5 6 — 630 ± 470 NA B — — B C 37.5 6 — 1420 ± 730  NA B— — Analysis Technique A Acyclovir skin permeation followed byextgraction from skin layers, dermis + epidermis/stratum corneum.Analysis Technique B epidermis/stratum corneum only. Analysis TechniqueC direct donor application to dermis.

TABLE 4 Acyclovir skin permeation studies: ethanol/water based vehicleAcyclovir Acyclovir Acyclovir flux Flux ratio Amount # retention --retention -- through (Compared to Formu- Applied cells epidermis dermisepidermis control of same lation (μL/cm2) (n) (μg/g) (Cv %) (μg/g) (Cv%) (μg/cm2 * hr)) (Cv %) Cells donor) F 120 6 135 ± 4  25.2 6 ± 2 33.30.68 ± 0.19 27.9 Crown 11.72 G 80 7 355 ± 80  22.5 257 ± 148 57.6 0.96 ±0.72 75.0 in-line 16.55 H 120 6 208 ± 109 52.4 21 ± 23 109.5 1.12 ± 0.2724.1 in-line 19.3 I 160 4 1490 ± 270  18.1 298 ± 296 99.3 1.36 ± 0.6447.1 in-line 23.4 J - Trial 1 160 4 796 ± 278 34.9 98 ± 30 30.6 1.62 ±0.70 43.2 Crown 27.9 K -- Trial 1 105 5 290 ± 221 76.2 222 ± 63  28.42.6 ± 0.8 30.8 in-line 44.8 J - Trial 2 160 6 912 ± 136 14.90 102 ± 333326.5 3.34 ± 0.95 28.4 Crown 57.6 K -- Trial 2 105 5 891 ± 478 53.6 1248± 1266 101.4 4.8 ± 2.9 60.4 in-line 82.8 L 160 4 728 ± 909 124.9 188 ±122 64.9 0.43 ± 0.09 20.9 Crown 7.41 M 105 5 356 ± 95  26.7 423 ± 457108.0 0.28 ± 0.24 85.7 in-line 4.83 N 160 5 459 ± 198 43.1 131 ± 95 72.5 0.57 ± 0.10 17.5 Crown 9.83 B (control) 105 5 211 ± 401 190.0 334 ±576 172.5 0.058 ± 0.055 94.8 in-line — All cells in Table 4 wereanalyzed via extraction Technique A

FIGS. 2-4 show the acyclovir flux profiles over time for eachformulation listed in table 2. The studies run in this group included acomparison of skin permeation across epidermis only, andepidermis+dermis (FIG. 2). Pegylated SNAC (MW approx. 601) was alsoevaluated as a delivery agent compound in these studies, results shownin FIG. 3. Results from a reformulated base of SNAC in an ethanol/watergel are shown in FIG. 4. An ethanol content of 50% or more appeared toproduce the highest acyclovir flux in this example at a factor of 9.8×Cicloferon, as shown in FIG. 5.

Flow thru cells converted to non-flow thru use were setup for permeationstudies in the radiolabeled lab. The cells were magnetically stirred,jacketed and kept at 33° C., and a pH 7.4 phosphate buffer was used asthe receptor. These cells have a recessed surface for placement of thetest membrane. Epidermis only was used in these cells for ³H acyclovirstudies. The epidermis was placed over 20 mm diameter 0.45 μm nylonfilter disks prior to mounting in the cell. The source of ³H acyclovirwas Sigma (#A1562, lots 104K9602 & 026K9600) with a specific activity of15 & 45 Ci/mmol respectively in a solution of 3/7 ethanol/water.

At the conclusion of the experiment, the epidermal membrane was removedand rinsed. Epidermal retention was determined for non-tritiatedacyclovir by tissue extraction in a buffer/methanol solution followed byHPLC assay. For ³H-acyclovir the tissue was dissolved by Soluene350/buffer followed by scintillation counting for calculation ofepidermal retention. Beta counting of all samples was performed bydiluting 0.5 ml of each sample with 1.0 ml of scintillation fluid(Perkin-Elmer Optiphase Hisafe II #1200-436). The extraction solvent forepidermal content was a 1:4 mixture of ph 7.4 buffer:tissue solubilizer(Perkin-Elmer Soluene 350 #600-3038).

³H Acyclovir Skin Permeation

Two PEG-based formulations were prepared, both formulations alsocontaining ˜7.5% ethanol by volume. The first formulation containedabout 5 wt % acyclovir (Formulation O) and the second formulationcontained about 5 wt % acyclovir and about 5 wt % SNAC (Formulation P).

Results of the ³H acyclovir skin permeation trials are set forth belowin Table 6:

TABLE 6 3H Acyclovir skin permeation studies with Cicloferon with andwithout SNAC Flux ratio Acyclovir Acyclovir Acyclovir (Comparedretention -- retention -- flux through to control Analysis cellsepidermis dermis epidermis Skin of same Technique Formulation (n) (μg/g)(μg/g) (Cv %) (μg/cm2 * hr)) (Cv %) Donor Cells donor) B O 3 21 ± 4 19.0 — 0.046 ± 0.006 13.0 C in-line — B P 5 37 ± 14 37.8 1.76 0.098 ±0.009 9.2 C in-line 2.13 B O 3 5 ± 2 40.0 — 0.011 ± 0.001 9.1 D in-line— B P 7 38 ± 37 102.7 7.6 0.011 ± 0.004 36.4 D in-line 1.00

The acyclovir flux profiles for both formulations are shown in FIGS. 12& 14. FIG. 13 shows the cumulative amount of acyclovir delivered. Theslopes were calculated by linear regression.

Acyclovir skin permeation of the control (Cicloferon) across all fourskin donors used in these studies is listed below in Table 7:

TABLE 7 Acyclovir retention and flux from control across all skin donorsAcyclovir Acyclovir Acyclovir flux # retention -- retention -- throughAnalysis cells epidermis dermis epidermis Skin Technique Formulation (n)(μg/g) (μg/g) (μg/cm2 * hr)) Donor Cells A B 4 160 ± 160 20 ± 30 0.023 ±0.015 A in-line B B 4 — — 0.60 ± 0.66 B Crown A B 5 211 ± 401 334 ± 5760.058 ± 0.055 C in-line B B (³H) 3 21 ± 4  — 0.046 ± 0.006 C in-line B B4 311 ± 383 — 0.017 ± 0.015 D in-line B B (³H) 3 5 ± 2 — 0.011 ± 0.001 Din-line type A (Analysis Technique) Acyclovir skin permeation followedby extgraction from skin layers, dermis + epidermis/stratum corneum.type B (Analysis Technique) epidermis/stratum corneum only.

The average values ranged from 0.011-0.60 μg/cm²-hr. The last skin donorlisted was used in several studies including ³H acyclovir formulations.The skin permeation result from the ³H acyclovir Cicloferon was 79% &65% (two skin donors) of the value obtained using the non tritiatedcontrol and conventional HPLC sample assay.

What is claimed is:
 1. A pharmaceutical composition comprising (a) about1% to about 10% by weight of acyclovir or a salt thereof; (b) a vehiclefor topical delivery comprising alcohol and water at a ratio of 1:1 to7:3; and a delivery agent compound which isN-(8-[2-hydroxybenzoyl]amino)caprylic acid or a salt thereof; whereinthe pharmaceutical composition is a topical pharmaceutical composition.2. The pharmaceutical composition of claim 1, wherein the delivery agentcompound is a sodium salt of N-(8-[2-hydroxybenzoyl]-amino)caprylicacid.
 3. The pharmaceutical composition of claim 1, wherein the vehiclefor topical delivery further comprises polyethylene glycol.
 4. Thepharmaceutical composition of claim 1, wherein the acyclovir or saltthereof component epidermal flux enhancement factor is 4 or higher. 5.The pharmaceutical composition of claim 1, further comprising one ormore additional active agents selected from anti-allergic medications,glucocorticoids, corticosteroids, anti-inflammatory agents, painrelievers, local anesthetics, and combinations thereof.
 6. Thepharmaceutical composition of claim 5, where the one or more additionalactive agents is selected from oxatamide, betamethasone, valerate,dexamethasone, triamcinolone acetonide, clobetasone butyrate,hydrocortisone, triamcinolone, flurbiprofen, ketorolace, lidocaine,benzocaine, articaine, chlorprocaine, cocaine, dydloninem, proparacaine,mepivacaine, prilocalne, procaine, tetracaine, pramoxin, andcombinations thereof.
 7. The pharmaceutical composition of claim 1,wherein the alcohol is ethanol.